Dyslipidemia and cardiovascular health in childhood nephrotic syndrome


Children with steroid-resistant nephrotic syndrome (SRNS) are exposed to multiple cardiovascular risk factors predisposing them to accelerated atherosclerosis. This risk is negligible in steroid-sensitive nephrotic syndrome, but a substantial proportion of children with SRNS progress to chronic kidney disease, exacerbating the already existing cardiovascular risk. While dyslipidemia is an established modifiable risk factor for cardiovascular disease in adults with NS, it is uncertain to what extent analogous risks exist for children. There is increasing evidence of accelerated atherosclerosis in children with persistently high lipid levels, especially in refractory NS. Abnormalities of lipid metabolism in NS include hypertriglyceridemia and hypercholesterolemia due to elevated apolipoprotein B-containing lipoproteins, decreased lipoprotein lipase and hepatic lipase activity, increased hepatic PCSK9 levels, and reduced hepatic uptake of high-density lipoprotein. Existing guidelines for the management of dyslipidemia in children may be adapted to target lower lipid levels in children with NS, but they will most likely require both lifestyle modifications and pharmacological therapy. While there is a lack of data from randomized controlled trials in children with NS demonstrating the benefit of lipid-lowering drugs, therapies including statins, bile acid sequestrants, fibrates, ezetimibe, and LDL apheresis have all been suggested and/or utilized. However, concerns with the use of lipid-lowering drugs in children include unclear side effect profiles and unknown long-term impacts on neurological development and puberty. The recent introduction of anti-PCSK9 monoclonal antibodies and other therapies targeted to the molecular mechanisms of lipid transport disrupted in NS holds promise for the future treatment of dyslipidemia in NS.


Idiopathic nephrotic syndrome (NS), characterized by severe proteinuria, hypoalbuminemia, edema, and hyperlipidemia, affects 1.15 to 16.9 per 100,000 children with the highest incidence among children with south Asian ancestry [1]. While the majority of these children are steroid responsive, approximately 10–20% remain unresponsive to steroids (steroid resistant, SRNS) and are both difficult to treat and prone to complications of unremitting NS [2]. Outcomes in SRNS are also far worse, with > 50% of those who fail to achieve remission progressing to end-stage kidney disease [2]. Hypercholesterolemia is a ubiquitous finding in NS and is almost always accompanied by various other abnormalities in lipid levels, as well as alterations in the composition and function of lipoproteins. The magnitude of dyslipidemia in NS is directly correlated with the severity of proteinuria [3]. Therefore, children with unremitting NS have marked dyslipidemia that likely greatly increases their risk for future cardiovascular complications. Long-term studies of adults with SRNS during childhood are lacking; therefore, it is not yet known whether dyslipidemia confers long-term cardiovascular risk from accelerated atherosclerosis in children with SRNS. However, increasing evidence of premature atherosclerosis, especially in children with refractory NS, highlights the need for careful attention to the assessment and management of cardiovascular risk associated with dyslipidemia. In this review, we summarize the pathophysiological mechanisms of altered lipid metabolism during NS and propose a therapeutic approach to dyslipidemia in refractory NS that has been adapted from the American Academy of Pediatrics and the National Heart, Lung, Blood Institute (NHLBI) guidelines [4].

Normal lipid metabolism

Lipids are a heterogeneous group of compounds that are insoluble in water. These include simple lipids such as fats (esters of fatty acid with glycerol); complex lipids such as phospholipids, glycolipids, and lipid precursors; and derived lipids such as fatty acids, glycerol, cholesterol, steroids, and hormones. Lipids are transported in the plasma as lipoproteins (Table 1). Lipoproteins comprise of a nonpolar lipid core of triglyceride or cholesteryl ester, which is surrounded by a layer of amphipathic phospholipid or cholesterol. The four major plasma lipoproteins include chylomicrons, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). Apolipoproteins are protein moieties that constitute 70% of HDL and 1% of chylomicrons. A lipoprotein can have one or more apolipoproteins, some of which are integral and cannot be removed (apolipoprotein B), whereas others are bound to the surface and can be transferred to other lipoproteins (apolipoprotein C and apolipoprotein E). Besides forming the structure of lipoprotein, apolipoproteins act as enzyme cofactors or inhibitors or serve as ligands for interaction with lipoprotein receptors (Table 2).

Table 1 Composition and function of lipoproteins
Table 2 Important regulatory proteins, receptors, ligands, and enzymes in lipoprotein metabolism

Lipid transport

Exogenous pathway

Dietary lipid is digested in the intestine to free fatty acids, triglycerides, cholesterol, and phospholipids, which are emulsified and mixed with bile salt micelles. About 50% of the dietary cholesterol is absorbed through intestinal enterocytes and is a major contributor to the total circulating cholesterol. Bile salt-emulsified triglycerides and cholesteryl ester are hydrolyzed by pancreatic lipase and carboxy ester lipase. Cholesterol is absorbed by a putative transporter, Niemann-Pick C1-Like-1 protein, across the brush border membrane into enterocytes in the jejunum and esterified (Fig. 1a). Triglycerides, cholesteryl esters, and phospholipids are transported within the lumen of the endoplasmic reticulum by microsomal triglyceride transfer protein and assembled with apoB-48 to form nascent chylomicrons that enter the bloodstream through the thoracic duct. In the plasma, nascent chylomicrons acquire apoC-II and apoE to form mature chylomicrons. Lipoprotein lipase, bound to the endothelium of capillaries in adipose and muscle tissues, is activated by apoC-II and hydrolyzes triglycerides contained within chylomicrons into free fatty acid that are utilized by these tissues. As chylomicrons lose triglycerides, they become enriched in apoE and generate chylomicron remnants in the process. The chylomicron remnants are subsequently taken up by hepatocytes by receptor-mediated endocytosis mediated by apoE-dependent receptors, LDL receptor, and LDL-related protein 1. In the liver, chylomicron remnants are hydrolyzed once again to free fatty acids and cholesterol, which are then used for VLDL synthesis.

Fig. 1

Physiological lipid transport and pathogenic mechanisms of dyslipidemia in nephrotic syndrome. a Dietary cholesterol is transported by Niemann-Pick C1-like-1 (NPC1L1) into enterocytes where lipidation of apoB-48 occurs with cholesteryl esters (CE), phospholipids, and triglycerides (TG) resulting in the formation of nascent chylomicrons ① Nascent chylomicrons accept apolipoproteins C (cofactor of the enzyme lipoprotein lipase) and apoE, from HDL ② forming chylomicrons (exogenous pathway). Lipoprotein lipase, anchored to the endothelial lining by glycosylphosphatidylinositol-anchored binding protein (GPIHBP1) ③, hydrolyzes TG within chylomicrons into free fatty acids (FFA) which are utilized by muscles and adipose tissues ④. This uptake of TG from chylomicrons forms chylomicron remnants ⑤ and apoC is recycled back to HDL ⑤. Similarly, TG synthesized in the liver is transported by VLDL (endogenous pathway ⑥) and hydrolyzed by lipoprotein lipase ⑦ into remnants (IDL) that are relatively rich in CE ⑧. Hepatic uptake of chylomicron remnants and IDL is mediated by LDL receptors (LDL-R) ⑨. Hydrolysis of TG and CE by hepatic lipase generates FFA and free cholesterol within the liver ⑩ that suppresses de novo synthesis of cholesterol by HMG-CoA enzyme ⑩. The majority of IDL is converted to LDL ⑪, which is taken up by the liver or extrahepatic tissues by LDL-R. LDL-R expression on the cell surface is tightly regulated, and its degradation within hepatocyte lysosomes is facilitated by PCSK9 ⑫. In the reverse cholesterol transport, HDL accepts free cholesterol from tissues via the ABCA1 receptor ⑬ and esterifies it to CE by lecithin:cholesterol acyltransferase (LCAT) within the HDL particles ⑭. CE is transported to the liver either directly by scavenger receptor B1 (SR-B1) receptors ⑮ or indirectly following transfer from HDL particles to other lipoproteins by cholesteryl ester transfer protein (CETP) ⑯. b In nephrotic syndrome, decreased lipoprotein lipase activity occurs due to downregulation of its anchor protein GPIHBP1 and upregulation of its inhibitor ANGPTL4 ①. In addition, there is diminished apoE, the principal ligand for VLDL and chylomicron binding to the endothelium ②. FFA delivery to tissues is thus compromised ③. Deficiency of hepatic lipase causes impaired clearance of TG-rich chylomicrons and VLDL, contributing to hypertriglyceridemia ④. PCSK9 is upregulated, causing destruction of LDL-R and impaired clearance of LDL ⑤. Hepatic HMG-CoA reductase is now no longer downregulated and acyl-CoA:cholesterol acyltransferase (ACAT) is upregulated for synthesis and esterification of free cholesterol within the liver ⑥. Heavy urinary losses and reduction of serum LCAT levels ⑦ impair esterification of free cholesterol to CE within HDL particles, resulting in inefficient extraction of cholesterol from tissues. SR-B1 deficiency leads to inadequate delivery of CE to the liver ⑧. Increased levels of CETP ⑨ cause depletion of CE within HDL, compounding the failure of reverse cholesterol transport (ABCA-1, ATP-binding cassette transporter A1; ANGPTL4, angiopoietin-like protein 4; ApoA, apolipoprotein A; ApoB-48, apolipoprotein B-48; ApoB-100, apolipoprotein B-100; ApoC, apolipoprotein C; C, cholesterol; CE, cholesteryl ester; ApoE, apolipoprotein E; FFA; free fatty acid; GPIHBP1, glycosylphosphatidylinositol-anchored binding protein 1; HDL, high-density lipoprotein; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; IDL, intermediate-density lipoprotein; LDL, low-density lipoproteins; LCAT, lecithin–cholesteryl ester acyltransferase; LDL-R, low-density lipoprotein receptor; LRP, LDL-receptor-related protein; MTP, microsomal triglyceride transport protein; NPC1L1, Niemann-Pick C1-like-1; PCSK9, proprotein convertase subtilisin/kexin type 9; SR-B1, scavenger receptor B1; VLDL, very low-density lipoprotein; TG, triacylglycerol)

Endogenous pathway

In the endogenous pathway, VLDL is synthesized in the liver and transported to peripheral tissues (Fig. 1a). Initially, small amounts of triglycerides, phospholipids, and cholesteryl ester are added to the newly synthesized apoB-100 to form a precursor VLDL; more triglycerides are subsequently transferred, forming a larger VLDL2. In the circulation, VLDLs acquire apoC-II and apoE from HDL and, upon lipolysis by lipoprotein lipase, release FFA to adipose and muscle tissue. On depletion of triglycerides and apoC-II, the VLDL particles are transformed into IDLs (intermediate density lipoproteins), which are either removed by the liver or develop into LDL on further lipolysis. Variations in the levels of VLDL, IDL, LDL, and HDL are dependent on the genetic composition of apoE. Uptake of cholesterol from LDL by peripheral tissues is facilitated by receptor-mediated endocytosis by the LDL receptor located on clatharin-coated pits. While endocytosis is tightly regulated, LDL cholesterol does not always reach the appropriate destination and can accumulate in arterial walls, causing atherosclerosis. The principal ligand for LDL receptor is apoB-100; however, apoE-containing lipoproteins such as VLDL, IDL, and HDL can also be endocytosed. After endocytosis, the apoprotein and cholesteryl ester are hydrolyzed in the lysosomes by liposomal lipase, and free cholesterol is released in the cell for incorporation into the cell membrane, as well as for the synthesis of steroids and bile acids. The influx of cholesterol into the cell inhibits both cholesterol synthesis by downregulation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, as well as synthesis of LDL receptor via the sterol regulatory element binding protein pathway. In addition, a protein called proprotein convertase subtilisin kexin type 9 (PCSK9) promotes degradation of the LDL receptor within cells and prevents its recycling to the cell membrane.

HDL and reverse cholesterol transport

HDL extracts cholesterol from tissues and transports it back to the liver for excretion directly into bile or conversion to bile acids for excretion. This process is termed the reverse cholesterol pathway, which is crucial to lipid homeostasis in humans (Fig. 1a). The chief protein component of HDL is apolipoprotein apoA-I, which forms the initial structure of the discoidal HDL. Cholesterol and phospholipids from peripheral tissues and atherogenic cells are transferred to HDL by ATP-binding cassette transporter A1. Cholesterol is packed into discoidal pre-HDL by lecithin–cholesterol acyltransferase, resulting in its maturation into spherical HDL3, which can continue to accept unesterified cholesterol. Cholesteryl ester transfer protein and phospholipid transfer protein are lipid transfer proteins that catalyze exchange of cholesterol between lipoproteins in the circulation. The former catalyzes the exchange of cholesteryl ester inside HDL for triglycerides of LDL and VLDL. In contrast, the latter facilitates the transfer of phospholipids and, to some extent, cholesterol from triglyceride-rich lipoproteins such as VLDL and chylomicrons to HDL. Phospholipid transfer protein also catalyzes the fusion of two HDL3 particles to form mature HDL2 while releasing apoA-I. Cholesterol-rich HDL is cleared by binding of HDL2 particles to the scavenger receptor class B type 1 protein (SR-B1) on hepatocytes, followed by efflux of cholesteryl esters into the cells without internalization of the entire particle. Thus, mature HDL is converted into lipid-poor pre-β-HDL and is recycled back for reverse cholesterol transport. Cholesterol delivered from HDL into the liver then enters into the bile acid synthesis pathway.

Mechanism of lipid abnormalities in nephrotic syndrome

Lipid abnormalities in NS are mostly due to impaired clearance of lipids than to increased biosynthesis (Fig. 1b). These include elevations in plasma levels of cholesterol, triglycerides, and apoB-containing lipoproteins (LDL, VLDL, and IDL) and lipoprotein(a). The plasma levels of HDL may be either normal or reduced. There are significant increases in the plasma levels of apoA-I, apoA-IV, apoB, apoC, and apoE, as well as the apoC-III to apoC-II ratio.

Impaired VLDL and chylomicron clearance and hypertriglyceridemia

Nephrotic syndrome results in deficiencies in peripheral tissue lipoprotein lipase activity, hepatic lipase activity, and hepatic VLDL receptors, as well as increased levels of cholesteryl ester transfer protein and lipoprotein receptor-related protein. Lipoprotein lipase, produced in myocytes, adipocytes, and other peripheral cells, catalyzes the hydrolysis of triglycerides in chylomicrons and VLDL. It is anchored to the endothelium of adjacent capillaries by endothelium-derived glycosylphosphatidylinositol-anchored binding protein (GPIHBP1), which also serves as a ligand to chylomicrons. In NS, there is downregulation of lipoprotein lipase and GPIHBP1 [5, 6]. In addition, there is reduction in apoE that is the principal ligand binding chylomicrons and VLDL to the endothelium. This is due to a paucity of cholesterol ester rich HDL2 which lends apoE and apoC to VLDL and chylomicrons in NS [7]. Further, apoC-II, a lipoprotein lipase activator, is reduced and apoC-III, which is its inhibitor, is increased in VLDL and chylomicrons [8, 9]. These abnormalities cause reduced lipolysis of VLDL and chylomicrons, resulting in hypertriglyceridemia, increased VLDL, impaired clearance of chylomicrons, and postprandial lipemia in NS. Hepatic lipase also plays a key role in the removal of triglyceride from IDL and efflux of cholesterol from HDL to hepatocytes. The deficiency of hepatic lipase activity in NS further contributes to hypertriglyceridemia [10].

Studies have shown that there is also upregulation of angiopoietin-like protein 4 (ANGPTL4) in NS [11]. ANGPTL4 inactivates lipoprotein lipase and inhibits hepatic lipase, resulting in impaired lipolysis of VLDL, chylomicrons, and hypertriglyceridemia [12]. In contrast to lipoprotein lipase that promotes delivery of fatty acids to adipocytes for storage, ANGPTL4 increases lipolysis of intracellular triglycerides in adipose tissue and increases free fatty acid levels, contributing to cachexia in NS [3, 13]. In addition, in NS, genes encoding for triglyceride and fatty acid synthesis are upregulated in the liver, contributing to hyperlipidemia [14].

Increased total cholesterol and LDL cholesterol

The nephrotic state is associated with markedly increased total cholesterol and LDL cholesterol levels, due to both impaired clearance and increased production. Animal studies have demonstrated that HMG-CoA reductase is increased in the liver during NS, resulting in increased cholesterol synthesis and hypercholesterolemia [15]. Studies in nephrotic animals have also shown that there is upregulation of acyl-CoA:cholesterol acyltransferase, which is responsible for esterification of free cholesterol and its packaging in apoB-100 in the liver, thus resulting in increased LDL levels [16]. Several studies have shown that there is impaired clearance and catabolism of LDL due to LDL receptor deficiency in NS [17,18,19]. PCSK9 (described above) and inducible degrader of the LDL receptor (IDOL) are the major posttranslational regulators of LDL receptor expression [18]. Levels of PCSK9 were shown to be elevated in patients with NS and anephric patients on peritoneal dialysis with hyperlipidemia, but not in those on hemodialysis [20], suggesting that protein loss in urine or peritoneal dialysate might be associated with elevated levels of PCSK9 [20]; there was a direct correlation between PCSK9 and LDL cholesterol levels. PCSK9 also interacts with CD36 or scavenger receptor class B type 3 which is an important receptor in macrophages for the uptake of oxidized LDL and promotes formation of lipid-laden foam cells and atherosclerosis.

Lipoprotein(a) [Lp(a)] is an LDL particle with covalently bound apoA. It is an atherogenic and prothrombotic factor that promotes LDL oxidation. There are marked increases in Lp(a) levels secondary to increased production in NS, which decrease with remission of proteinuria [21]. Lp(a) is a component of the total LDL cholesterol that is measured routinely and is also not reduced by statin therapy [22].

Impaired HDL-mediated reverse cholesterol transport

During NS, HDL-mediated reverse cholesterol transport is impaired, which in turn promotes atherogenesis. There is dysregulation of several key proteins in NS which results in abnormal structure and function of HDL cholesterol. There is also deficiency of the enzyme lecithin–cholesterol acyltransferase in NS, due to its loss in the urine [23]. This enzyme extracts cholesterol from macrophages and causes transformation of pre-HDL to cholesteryl ester-rich HDL. Further, HDL receives a significant amount of cholesterol from albumin. Hypoalbuminemia in NS contributes to impaired cholesterol enrichment of HDL [24]. Cholesteryl ester transfer protein mediates transfer of cholesteryl ester from HDL to IDL and LDL in exchange for triglycerides; serum levels of this protein are markedly increased in NS, promoting depletion of cholesteryl ester and enrichment of triglyceride in HDL [25]. There is also a deficiency of SR-B1 receptor expressed in hepatocytes, which results in impaired unloading of the cholesterol from HDL to the hepatocytes and hydrolysis of triglycerides and phospholipid by hepatic lipase [26]. This may be mediated by reduced expression of PDZ-containing kidney protein-1, which prevents the degradation of SR-B1 [27]. Recently, it has been shown that there is also marked upregulation of hepatic HDL endocytic receptor in NS, which mediates degradation of apoA-I and lipid-poor HDL [28]. Hepatic lipase deficiency also contributes to triglyceride-rich HDL in NS.

Dyslipidemia, cardiovascular health, and renal injury in nephrotic syndrome

The epidemiological association between cardiovascular risk factors and early signs of atherosclerosis has largely been derived from postmortem studies in children and young adults with accidental death, including The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study [29] and the Bogalusa Heart Study [30]. Early signs of atherosclerosis evaluated in these studies included fatty streaks that subsequently progressed to fibrous plaques in the intimal surface of the aorta and coronary vessels. Results of the Bogalusa cohort have shown strong correlations between antemortem levels of total and LDL cholesterol and the extent of atherosclerosis [30]. The PDAY study, a multicenter cross-sectional study of 2876 patients between 15 and 34 years old, found that the extent of fatty streaks was positively associated with postmortem LDL cholesterol (LDL-C), VLDL cholesterol (VLDL-C), and non-HDL cholesterol (non-HDL-C) concentrations and negatively associated with HDL-C concentrations [29]. Both these studies demonstrated an association between the number of cardiovascular risk factors and severity of atherosclerosis. To date, there are no data directly linking dyslipidemia in childhood to myocardial infarction, stroke, and mortality in adults. However, dyslipidemia during childhood and young adulthood is associated with noninvasive markers of atherosclerotic vascular disease. One study showed that LDL-C concentrations among children 8–18 years of age predicted carotid intima media thickness (cIMT) between 33 and 42 years of age [31]. In addition, a follow-up study of the Bogalusa cohort found that LDL-C concentrations during childhood predicted cIMT at the age of 16–19 years [32]. The Coronary Artery Risk Development in Young Adults study prospectively evaluated more than 2800 adults aged 18–30 years and found that cumulative exposure to nonoptimal concentrations of LDL-C (> 100 mg/dl) were independent predictors of increased coronary calcium scores two decades later [33].

Thus, while there is evidence to suggest that the atherosclerotic process may have its origins during childhood and that dyslipidemia is a risk factor, long-term follow-up studies in children with NS are not yet available. In addition to dyslipidemia, patients with NS are exposed to other cardiovascular risk factors, including hypoalbuminemia, a hypercoagulable state, hypertension, and steroid-induced obesity that further contribute to the development of atherosclerotic lesions [34]. While these abnormalities persist in children with SRNS due to their having a prolonged nephrotic state, they resolve in patients who enter spontaneous or steroid-induced remission [35], resulting in negligible cardiovascular risk in steroid-responsive patients. In a retrospective study, 62 adults with sustained remission of steroid-responsive or steroid-dependent NS for two to four decades had similar rates of cardiovascular events to the general population [36]. While children having frequent relapses experience prolonged periods of hypercholesterolemia [37], the long-term clinical consequences of this remain unclear. In contrast, NS in adults is known to confer a six-fold increased risk for myocardial infarction and three-fold increased risk for cardiovascular mortality [38]. In adults with NS, Lp(a) [39] and markers of endothelial dysfunction [40] are both involved in the complex process of atherosclerotic vascular disease and have been shown to remain elevated, even following disease remission. Although long-term prospective studies evaluating evidence of cardiovascular morbidity in children with SRNS are lacking, the American Heart Association Pediatric Consensus Guidelines has designated NS as a “special risk category” for accelerated atherosclerosis, compelled by evidence of vascular dysfunction demonstrated by noninvasive means [4, 41]. In support of this, a study of 37 children with SRNS showed evidence of subclinical cardiovascular disease in 5–22% of patients, assessed by abnormal aortic pulse wave velocity, elevated cIMT, and increased left ventricular mass index [42]. This increased risk was independently associated only with higher LDL-C levels [42].

Dyslipidemia is an important modifiable risk factor that may also aggravate glomerulosclerosis and contribute to the progression of renal injury [43, 44]. In the Chronic Kidney Disease in Children (CKiD) cohort, the presence of dyslipidemia was associated with a 40% shorter time to the composite outcome of requirement of renal replacement therapy or 50% reduction in estimated GFR in patients with non-glomerular disease [45]. Dyslipidemia may also induce direct cellular injury to both renal proximal tubular epithelial cells and podocytes in NS [46]. Another important clinical consequence of dyslipidemia in refractory NS is its contribution to the known increased risk for thromboembolism. Levels of oxidized LDL and markers of oxidative stress have been shown to be significantly elevated in children with active NS [47]. While the precise mechanisms by which dyslipidemia contributes to thrombus formation are still unclear [48], it is postulated that oxidatively modified LDL products may enhance platelet activation and thrombus formation in NS.

Screening and monitoring for dyslipidemia in nephrotic syndrome

The NHLBI guidelines recommend universal screening of children for hyperlipidemia at ages 9 and 11 years and earlier (between 2 and 8 years) in at-risk children including those with NS [4]. Two fasting lipid profiles 2 weeks to 3 months apart are recommended, with abnormal tests confirmed on a repeat measurement. Table 3 shows cutoffs of lipid levels that have been adopted by the NHLBI guidelines and are widely accepted in clinical practice. However, fixed thresholds that ignore cholesterol variations by age and sex may be problematic.

Table 3 Cut-off values (mg/dl) for abnormal lipid levels and targets during therapy according to NHLBI guidelines [4]

Whereas hyperlipidemia is invariably present in refractory NS, lipid abnormalities are unlikely to be abnormal during sustained remission in children with steroid-sensitive NS. Total cholesterol levels are routinely obtained in children with NS, although a complete lipid profile is recommended in those with SRNS. The baseline lipid profile for children with SRNS should include total cholesterol, triglyceride, HDL-C, LDL-C, and non-HDL-C. When available, apoB and Lp(a) may also be assessed [49]. While obtaining a lipid profile following a 10–12-h fast is standard, current guidelines suggest that non-fasting lipid levels can be utilized for screening because they show comparable results for total cholesterol, LDL-C, and HDL-C, with only a small increase (± 20%) in triglycerides [49]. Patients with NS with hypertriglyceridemia may require a fasting sample for accurate estimation of LDL-C. In clinical practice, LDL-C is either estimated directly or calculated by the Friedewald formula as follows [50]:

$$ \left[\mathrm{LDL}\ \mathrm{cholesterol}\ \left(\mathrm{mg}/\mathrm{dl}\right)=\mathrm{Total}\ \mathrm{cholesterol}-\mathrm{HDL}\ \mathrm{cholesterol}-\mathrm{plasma}\ \mathrm{triglyceride}/5\right] $$

Direct measurement of LDL-C does not require a fasting sample but does incur additional costs [49]. The Friedewald formula has significant limitations; errors in LDL-C become magnified with triglycerides > 200 mg/dl and the calculation is not valid for samples having triglycerides > 400 mg/dl [49]. A modification of this equation was published by Martin and colleagues to improve the accuracy of estimating LDL-C [51]:

$$ \left[\mathrm{LDL}\ \mathrm{cholesterol}=\mathrm{Total}\ \mathrm{cholesterol}-\mathrm{HDL}\ \mathrm{cholesterol}-\mathrm{plasma}\ \mathrm{triglyceride}/\mathrm{adjustable}\ \mathrm{factor}\right] $$

where the adjustable factor is the strata-specific median triglyceride:VLDL-C ratio. This method provided the best estimate of LDL-C in the presence of high triglyceride levels [49], as are often encountered in refractory NS.

In children with NS, target lipid levels on therapy should be individualized based on their cardiovascular risk assessment (Table 3). Patients with refractory NS who progress to chronic kidney disease (estimated glomerular filtration rate below 60 ml/min/1.73 m2 for 3 months) constitute a high-risk group where lower lipid levels should be targeted [4]. Following initiation of lipid-lowering drug treatment or modification of ongoing therapy, a second lipid panel should be performed 4–12 weeks later. Subsequent assessments should also be performed every 4–12 weeks until the target lipid levels are achieved, followed by yearly assessments [49].

Treatment of dyslipidemia in nephrotic syndrome

This review focuses primarily on the screening and management of dyslipidemia in patients with NS, which is an integral part of a comprehensive strategy for cardiovascular risk reduction including the following [52]:

  1. 1.

    Minimize proteinuria (specific therapy; renin angiotensin aldosterone system blockade)

  2. 2.

    Control of blood pressure, preferably ambulatory blood pressure to < 50th centile for age and sex; assess for left ventricular hypertrophy and cardiac dysfunction

  3. 3.

    Weight reduction to achieve body mass index (BMI) < 85th centile for age and sex

  4. 4.

    Achieve target lipid levels (Table 3)

  5. 5.

    Achieve fasting glucose levels (< 100 mg/dl and HbA1c < 7%)

  6. 6.

    Minimize tobacco exposure

Lifestyle modifications

Whether primary or secondary to disease, the first step in the treatment of dyslipidemia and reducing other cardiovascular risk factor is nonpharmacological lifestyle modification. It includes dietary modification, enhanced physical activity, and avoidance of smoking. Adoption of these lifestyle modifications by the whole family is recommended for optimal compliance.

Dietary modification

The NHLBI recommends Cardiovascular Health Integrated Lifestyle Diet (CHILD-1) as the first step as dietary modification in children > 2 years of age with dyslipidemia. This diet includes restricting saturated fat intake to < 10% of the total caloric intake and cholesterol to < 300 mg/day, with sufficient calories to maintain normal growth and development. Dietary fat is not restricted for children ≤ 2 years of age, and breast feeding is allowed for infants. In children with hypercholesterolemia, the CHILD-2 intervention is recommended, which further limits dietary fat to < 7% of total caloric intake and cholesterol to < 200 mg/day. Trans fats should also be avoided as much as possible. Data on the safety and efficacy of dietary fat modification in children is limited to two randomized controlled trials that suggested efficacy for this approach in lowering cholesterol levels and noninterference with normal growth and development [53, 54]. Fiber, omega 3 fatty acids, and plant stanols and sterols may have an additional benefit [55]. For total cardiovascular risk reduction, a diet as per local food habits including fruits, vegetables, legumes, nuts, and whole grain cereal foods should be encouraged, and trans or saturated fat intake (hard margarines, tropical oils, fatty or processed meat, sweets, cream, butter, regular cheese) should be discouraged or replaced with monounsaturated fat (extra virgin olive oil) and polyunsaturated fat (nontropical vegetable oils) [56]. Salt intake should be reduced to < 2.3 g/day in children with hypertension by choosing fresh or frozen unsalted food, since many processed and convenience foods are high in salt [57]. The intake of beverages and foods with added sugars, particularly soft drinks, should also be limited, and tobacco exposure avoided [56]. To facilitate adherence with these guidelines, a leaflet on healthy eating detailing these guidelines should be made available to patient and their families [58].

Enhanced physical activity

There is strong evidence to suggest that increased physical activity reduces cardiovascular risk factors such as blood pressure, BMI, and blood glucose and might also improve levels of HDL-C and triglycerides in children [4, 55, 59]. The NHLBI guidelines recommend limiting leisure screen time (computer, video games, television, etc.) to < 2 h/day, moderate-to-vigorous activity for at least 1 h/day, and vigorous activity for at least 3 days/week for children > 5 years of age [4].

Pharmacological treatment

Due to the lack of good quality evidence, there are no clear recommendations on pharmacotherapy for hyperlipidemia in pediatric NS. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines note that hyperlipidemia in NS be treated according to the guidelines for high-risk individuals for developing cardiovascular disease, particularly when the disease cannot be ameliorated. It also suggests that dietary restrictions have only modest effects and suggests drug therapy be used [60]. The indications for pharmacotherapy in children with NS are shown in Fig. 2.

Fig. 2

Proposed interventions for dyslipidemia in refractory nephrotic syndrome. aHigh-risk factors: chronic kidney disease stages 3 or more, stage 2 hypertension and body mass index (BMI) ≥ 97th centile; moderate risk factors: stage 1 hypertension and BMI > 95–97th centile (in addition to nephrotic state that itself imposes a moderate risk). bFamily history: parent, grandparent, aunt, uncle, sibling with a history of cardiovascular disease before 55 years of age in males and 65 years of age in females. cGrade of recommendations (in parenthesis) is based on the National Heart, Lung, and Blood Institute guidelines [4]. dMonitoring of lipid profile and statin therapy is adopted from the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) 2016 guidelines [56] (ALT, alanine aminotransferase; BMI, body mass index; BP, blood pressure; CK, creatinine kinase; ECHO, echocardiography; HDL, high-density lipoprotein; LDL, low-density lipoproteins; RF, risk factor; ULN, upper limit of normal)

Issues with pharmacotherapy in children with nephrotic syndrome

While studies have shown that hyperlipidemia in NS is associated with markers of premature atherosclerosis [42, 61], its effect on long-term cardiovascular morbidity and mortality remains unclear. While there are well-designed studies demonstrating that drug therapy reduces cholesterol levels in children, there are no data from randomized controlled trials in children with NS demonstrating these long-term benefits. Therapy to lower lipid levels would likely be indicated as long as children continue to have active nephrotic syndrome, raising concerns for long-term safety of drugs and issues with adherence to recommended therapy. An important potential concern with lipid-lowering drugs is the long-term impact on neurological development and puberty, since lipids are necessary for brain development and are also building blocks for steroid hormones such as estrogen and testosterone.


Statins inhibit hepatic HMG-CoA reductase. They inhibit cholesterol synthesis and upregulate LDL receptors, leading to clearance of atherogenic LDL-C and apoB-containing lipoproteins from the circulation [3]. Statins have demonstrated long-term safety and efficacy to reduce LDL-C by 25–35% in children with familial hypercholesterolemia (FH) [62, 63]. Beneficial effects on endothelial dysfunction, reflected by reduced progression of cIMT and improved flow-mediated dilation (FMD) of the brachial artery, have also been reported in patients with both FH [63] and NS [64] treated with statins. Statins and their doses approved for use in children after 8 to 10 years of age by the United States Food and Drug Administration (FDA) are presented in Table 4. While randomized trials on statin use have reported fewer younger children 4–10 years of age who seem to have had no or only very minor side effect [65,66,67,68], we do not have enough data yet to know the long-term safety of statins in younger children.

Table 4 Lipid-lowering drugs used in children

Unfortunately, there are limited data on the role of statins in treating the dyslipidemia associated with refractory NS (Table 5). Experience in the pediatric age group is limited to only two prospective uncontrolled studies demonstrating declines in triglycerides, LDL-C, and total cholesterol by 30–40%, occurring by 6–12 months, in 19 patients over a period of 6–60 months [69, 70]. In adults with nephrotic range proteinuria, studies demonstrating the beneficial effects of statins included a clinically heterogeneous populations including postrenal transplant [71], lupus nephritis [71, 72], Alport syndrome [73], interstitial nephritis [73], and idiopathic membranous nephropathy [74], limiting the generalizability of these results to children with NS that is predominantly due to minimal change disease or focal segmental glomerulosclerosis. While American and Japanese guidelines on childhood NS and the American Academy of Pediatrics Dyslipidemia Guidelines recommend considering statins in NS with persistently high fasting LDL cholesterol [4, 75, 76], evidence from randomized trials evaluating the use of statins in children with SRNS is scarce. A Cochrane systematic review of randomized trials including 191 adults with idiopathic NS failed to demonstrate superiority of statins over placebo in reducing total and LDL cholesterol [77]; however, most results were based on single study data, and the trials included were at high risk of reporting and selection bias.

Table 5 Studies of statins in nephrotic syndrome

In a prospective, randomized, double-blind, placebo-controlled trial, we examined whether a fixed dose of 10 mg atorvastatin was effective in improving dyslipidemia, cIMT, and brachial artery FMD in children 5–18 years of age with refractory NS [68]. After 12 months of treatment, we found that atorvastatin was not superior to placebo in reducing plasma LDL-C levels, with median percentage LDL-C reductions of 15.8 and 9.5%, respectively, in the atorvastatin and placebo arms (n = 14/group; P = 0.40). We also found no significant effects on other lipid fractions, and that the adverse events were similar between the groups. Changes in serum albumin levels were negatively associated with changes in serum LDL-C, very low-density lipoprotein cholesterol, total cholesterol, triglyceride, and apoB (P < 0.001), irrespective of receiving atorvastatin, age, gender, body mass index, and serum creatinine, suggesting that therapy to raise serum albumin (i.e., induce partial or complete remission) may instead be useful [68]. While this was the first randomized controlled trial of statins in pediatric patients with NS, longer, adequately powered studies and with statin dosing titrated to LDL-C levels and/or body surface area will be required to definitively determine if statins might be both safe and effective in children with unremitting NS. However, it seems unlikely that statin alone would be able to lower lipids to target levels in NS, and additional therapies may be required (Fig. 2).

Structural and functional abnormalities on vascular imaging in NS, assessed respectively by ultrasonographic measurements of increased cIMT [41, 83] and reduced FMD of the brachial artery [61], represent among the earliest stages of atherogenesis. A previous open-label study showed improvement in brachial artery FMD following atorvastatin in 8 of 10 adults with NS that was significantly correlated with reductions in non-HDL-C [64]. Unfortunately, a paucity of information exists on serial cIMT and FMD measurements in children with renal diseases, especially NS. We observed a median decline in cIMT by 0.004 mm/year in our recent study, that may have been due to dietary modifications and/or angiotensin-converting enzyme inhibition [68]. Our finding of no significant improvement in brachial artery FMD in this study may be explained by the insignificant changes in lipid levels we observed with statin treatment [68]. In another trial, 10 mg/day of atorvastatin also failed to change FMD (9.8 to 8%) in 8 children with CKD over 8 weeks [84].

While the safety of statins has been extensively examined in adults, there is some concern that when initiated in very early childhood it may adversely affect the nervous system, immune function, the hormonal milieu, and other systems. A 10-year follow-up study in children with FH showed that there was good adherence to statin therapy and that side effects were uncommon, consisting chiefly of gastrointestinal and muscle complaints [85]. While there is also a fear of fetal harm with statins, a systematic review suggested that these drugs are unlikely to be teratogenic [62].

Creatinine kinase (CK) and transaminase levels should be monitored during statin therapy. If CK levels increase to > 10 times normal levels or transaminase levels increase to > 3 times the upper limit of normal, treatment should be stopped. Of note, several drugs such as calcineurin inhibitors, azole antifungal agents, erythromycin, and gemfibrozil by inhibiting the CYP3A4 enzyme can predispose to statin-induced muscle injury [56]. Pravastatin and rosuvastatin may be better choices when these other drugs are being administered, since they do not require the CYP3A4 pathway for metabolism [56]. Patients treated with statins should be instructed to promptly report any symptoms of muscle aches or cramping to their treating physician.

Bile acid sequestrants

Bile acid sequestrants bind bile acids and inhibit their reabsorption in the ileum. This results in increased bile acid synthesis, reduced intrahepatic cholesterol, and increased LDL clearance from the circulation by upregulation of LDL receptors. These agents are not absorbed in the circulation and, therefore, have been used extensively in children. However, they are associated with significant gastrointestinal side effects such as flatulence and/or constipation, often resulting in their discontinuation. These agents can also increase triglyceride levels and interfere with absorption of fat-soluble vitamins. Randomized controlled trials of cholestyramine and colestipol have been shown to reduce total cholesterol levels by 7–12% and LDL cholesterol levels by 10–20%, but resulted in modest elevations in triglyceride levels in children with FH [86,87,88,89]. In adults with NS, two small trials reported reductions in LDL-C by 20–30% using these agents [72, 90]. Colesevelam, a second-generation bile acid sequestrant, was also reported to reduce LDL cholesterol by 7–13% in children with FH [91]. This treatment reportedly had good compliance and few reported side effects and is currently the only bile acid sequestrant to be approved by the US FDA for use in children [91].

Cholesterol absorption inhibitors

Cholesterol absorption inhibitors block the Niemann-Pick C1-like receptor in the intestine and thus inhibit the absorption of dietary and biliary cholesterol. Decreased cholesterol delivery to the liver results in increased uptake of cholesterol in the hepatocyte via upregulation of LDL receptors, thus increasing LDL cholesterol clearance from the circulation. Ezetimibe has been shown to reduce total cholesterol and LDL cholesterol in children with FH, either alone or in combination with statins [92]. A randomized controlled trial of a combination of ezetimibe with simvastatin reported a 38% reduction in total cholesterol and a 49% reduction in LDL cholesterol levels in children with FH, without significant reported side effects [93]. Due to its safety, it is likely to be a favored drug for use in young children.

Fibric acid derivatives

Fibric acid derivatives act as agonists of peroxisome proliferator-activated receptor-α (PPAR), which upregulates LPL and downregulates apoC-III, resulting in increased degradation of VLDL-C and triglycerides. They also stimulate cellular fatty acid uptake and oxidation, which, combined with a reduction in triglyceride synthesis, results in a decrease in VLDL production. Fibric acid derivatives mainly decrease triglyceride and increase HDL levels, with variable effects on LDL cholesterol levels. The reported side effects are primarily gastrointestinal, although rhabdomyolysis and myopathy can occur, particularly when used with statins. Unfortunately, the data on the use of fibric acid derivatives in children are very sparse. Benzafibrate has been reported to reduce total cholesterol by 22%, triglycerides by 23%, and increase HDL cholesterol by 15% in a small randomized control trial in children as young as 4 years old [94]. Benzafibrate was also reported to result in improvement of lipoprotein nephropathy in a child with NS [95]. Another derivative, gemfibrozil, along with diet and exercise reduced triglyceride levels by 54% and increased HDL cholesterol levels in children with metabolic syndrome [96]. In a small, randomized placebo-controlled trial, gemfibrozil decreased total cholesterol levels by 34%, LDL cholesterol levels by 30%, and triglyceride levels by 54% in children with NS [97]. However, a meta-analysis found this reduction to be similar to placebo [77]. Fibric acid derivatives may be useful in children with severe hypertriglyceridemia (> 500 mg/dl) in NS to prevent pancreatitis.


Niacin is a B complex vitamin that inhibits the release of FFA from adipose tissues and decreases the production of VLDL in the liver, resulting in decreases in LDL cholesterol and triglyceride levels. It also decreases the degradation of HDL cholesterol and reduces Lp(a) levels. In a small observational study in children between 4 and 14 years of age, it significantly reduced total and LDL cholesterol levels, although triglyceride and HDL levels remained unchanged [98]. However, the drug was poorly tolerated, with the majority of children developing flushing and transaminitis, which ultimately resulted in discontinuation of treatment in more than one-third of patients. Due to this poor reported tolerability, this treatment is not routinely recommended for use in children.

Omega 3 fatty acids

Omega 3 fatty acids are not synthesized in humans, and fish is its chief dietary source. Eicosapentaenoic acid and docosahexaenoic acid (DHA) have been found to reduce triglyceride levels by 30–40% and decrease LDL cholesterol and increase HDL cholesterol levels in adults [99]. Omega 3 fatty acids are believed to decrease fatty acid triglyceride synthesis in the liver and increase fatty acid degradation and oxidation, resulting in reduced VLDL release. A recent small, randomized controlled trial of DHA in children between 10 and 19 years of age reported no difference from placebo treatment in reducing triglyceride levels [100]. The EARLY study showed that while the LDL subclasses 3 decreased in the DHA group compared to placebo, there was no significant change in LDL cholesterol and triglycerides in children 9–19 years of age [101]. The drug is well tolerated with only occasional adverse gastrointestinal effects. In a study of 48 children with steroid-sensitive NS treated with and without omega 3 fatty acid, there was no significant difference in lipid levels between the groups [102].

LDL apheresis

LDL apheresis is an extracorporeal blood purification therapy that removes apoB-containing lipoproteins from the blood. LDL apheresis systems use negatively charged dextran sulfate columns (MAO3 Liposorber; Kaneka, Osaka, Japan) or heparin with low pH buffer solution (Futura; B.Braun, Melsungen, Germany) to selectively remove positively charged apoB lipoproteins. Long-term cohort studies in adults over 5–6 years have demonstrated the ability of LDL apheresis to deplete LDL-C and Lp(a) levels by 60–65 and 68–72%, respectively, in FH [103]. Various guidelines recommend LDL apheresis as first-line treatment in patients with homozygous FH and after drug therapy failure in patients with heterozygous FH [104]. While the use of LDL apheresis in children with refractory NS has been shown to reduce total cholesterol levels by 50% [105], 12 sessions of LDL apheresis (60 ml/kg exchanges; twice a week for 3 weeks then weekly for 6 weeks) also demonstrated a remarkable ability to induce long-term complete (45%) or partial (18%) remission of NS [105]. In 2013, LDL apheresis was approved by the US FDA for the treatment of resistant primary or postrenal transplant recurrent focal segmental glomerulosclerosis in children having glomerular filtration rates > 60 ml/min/1.73 m2 [103]. Similar results have been reported in the prospective multicenter POLARIS trial in adults, which reported a nearly 50% reduction in total cholesterol and LDL cholesterol levels [106], associated with complete or partial remission in one-half of patients [107]. Postulated mechanisms of its ability to induce remission of NS are direct effects related to lipid adsorption, removal of inflammatory cytokines or vascular permeability factors, and amelioration of intracellular transport of immunosuppressants enhancing their efficacy [103]. PCSK9, a relevant enzyme in the complex renal–hepatic axis in NS, has also been reported to decrease by up to 40% following LDL apheresis [108]. Thus, although invasive and expensive, LDL apheresis appears to hold significant promise to be able to induce early remission and rapid relief of dyslipidemia in at least some children with refractory NS.

Future perspectives

Podocyte damage in NS upregulates serum PCSK9, which degrades LDL receptors and results in hyperlipidemia [109]. This state of acquired LDL receptor deficiency may hamper the action of statins, which act by upregulation of LDL receptors [110]. Anti-PCSK9 antibodies inactivate PCSK9, promoting upregulation of LDL receptors and subsequently uptake of LDL in the liver. Two monoclonal antibodies targeting PCSK9, evolocumab and alirocumab, have been recently approved by the US FDA in adults, which reduce LDL-C by 50–70%, along with reduction of cardiovascular events [111, 112]. In addition, a recent publication reported a patient with refractory NS responding to this novel therapy [113]. This finding suggests that PCSK9 inhibitors may hold promise for the treatment of NS, since they act on the complex renal–hepatic axis that regulates plasma cholesterol [114]. In addition, a phase 2 clinical trial (NCT03004001) is now underway to assess the effect of combined therapy with alirocumab + atorvastatin vs. atorvastatin alone in adults with dyslipidemia secondary to NS. Trials on the safety of monoclonal antibodies to PCSK9 in the pediatric population are also ongoing (NCT02624869, in familial hypercholesterolemia).

Direct inhibition of CETP is another novel approach to increase HDL-C. However, randomized trials on these agents have not yet yielded beneficial results. Torcetrapib was withdrawn due to excess mortality, and a trial of evacetrapib was terminated due to futility, while dalcetrapib was found to be ineffective. A phase III trial with anacetrapib is currently underway [56]. Other areas of ongoing research include the use of apoB antisense antibodies to reduce production of apoB-related lipoproteins—VLDL and LDL (mipomersen), thyroid mimetics (eprotirome), acetyl-CoA acetyltransferase (ACAT) inhibitors (avasimbibe), microsomal triglyceride transfer protein inhibitor (lomitapide), and apoA1 mimetic peptides [46, 55, 56]. Mipomersen has been tested in patients as young as 12 years of age but approved by only the FDA in homozygous FH patients > 18 years of age [115]. Currently, lomitapide has been approved by the FDA as an adjunct to other therapies in adults with homozygous FH [115], and a phase 2 study has been performed in children > 13 years of age (NCT01556906).


Long-term prospective studies in children with NS, especially refractory NS, are required to better assess the effects of cardiovascular risk factors such as dyslipidemia on future cardiovascular morbidity and mortality. Due to growing evidence suggesting its association with accelerated atherosclerosis, however, routine surveillance of dyslipidemia should be considered essential in patients with refractory NS. Target lipid levels should be individualized according to cardiovascular risk profiles, and strategies including lifestyle modification most likely combined with pharmacological therapy will be required for clinically effective management. Well-controlled prospective trials on both current and future therapies for dyslipidemia in children with NS are needed. Novel therapies like PCSK9 inhibitors and LDL apheresis are promising new approaches that both require further examination.

Self-assessment questions (answers following the reference list)

  1. 1.

    Which of the following occurs during normal lipid metabolism?

  1. a)

    VLDL acquire apoC-II and apoE from HDL

  2. b)

    LDL cholesterol uptake occurs by LDL receptor in peripheral tissues

  3. c)

    Influx of cholesterol into the cell downregulates HMG-CoA reductase

  4. d)

    PCSK9 promotes recycling of LDL-R to the cell membrane

  1. 2.

    Dyslipidemia in nephrotic syndrome is characterized by:

  1. a)

    Elevated apoB-containing lipoproteins

  2. b)

    Elevated lipoprotein(a)

  3. c)

    Elevated HDL-C

  4. d)

    Increased apoA-I, apoA-IV, and apoC-III to apoC-II ratio

  1. 3.

    The pathophysiology of dyslipidemia in nephrotic syndrome involves which one of the following?

  1. a)

    Decreased lipoprotein lipase activity occurs due to downregulation of its anchor protein GPIHBP1 and upregulation of its inhibitor ANGPTL4

  2. b)

    PCSK9 is downregulated, causing destruction of LDL-R and impaired clearance of LDL-C

  3. c)

    Hepatic HMG-CoA reductase is downregulated and ACAT is upregulated

  4. d)

    ANGPTL4 activates LPL, resulting in lipolysis of VLDL and hypertriglyceridemia

  1. 4.

    Which statement regarding lipid profile assessment in children with nephrotic syndrome is incorrect?

  1. a)

    Friedewald formula is used for estimation of LDL-C in patients with TG > 400 mg/dl

  2. b)

    Screening lipid profile may be performed in the fed state

  3. c)

    Direct measurement of LDL-C is prone to errors

  4. d)

    Acceptable LDL-C for patients with SRNS is < 130 mg/dl

  1. 5.

    Which of the following is true regarding safety and tolerability of statins in children?

  1. a)

    Long-term safety of statins have not been established in young children

  2. b)

    Co-administration with gemfibrozil can predispose to statin-induced muscle injury

  3. c)

    Therapy should be stopped if creatinine kinase levels exceed > 10 times normal or transaminase levels increase to > 3 times the upper limit of normal

  4. d)

    Pravastatin and rosuvastatin require the CYP3A4 pathway for metabolism and predispose to drug interactions


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Answers 1. a, b, c; 2. a, b, d; 3. a; 4. a, c, d; 5. a, b, c

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Hari, P., Khandelwal, P. & Smoyer, W.E. Dyslipidemia and cardiovascular health in childhood nephrotic syndrome. Pediatr Nephrol 35, 1601–1619 (2020). https://doi.org/10.1007/s00467-019-04301-y

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  • Steroid-resistant nephrotic syndrome
  • Hydroxymethylglutaryl-CoA reductase inhibitors
  • Lipid metabolism
  • Hypolipidemic agents